Macrophages and related cell types play critical roles in immunity but also contribute significantly to the pathogenesis of a number of human diseases that involve chronic inflammatory responses. Monocyte-derived macrophages are involved in all stages of atherosclerosis, from the initial development of foam cell-rich fatty streak lesions to the rupture of complex, vulnerable plaques that result in myocardial infarction and stroke. Recent studies also indicate that adipose tissue macrophages secrete factors that promote insulin resistance in obesity. The macrophage itself is thus a potential target of therapeutic intervention. A major goal of the LIPID MAPS Consortium will be to characterize alterations in the macrophage lipidome and transcriptome in models of atherosclerosis and insulin resistance. Previous studies have demonstrated that drugs that activate the peroxisome proliferator-activated receptor y (PPARy) exert some of their protective effects in both of these disease states by regulating PPARy activity in the macrophage, but the underlying target genes and mechanisms remain unknown. This Bridge project will build upon the integrated studies proposed by the LIPID MAPS Consortium to specifically evaluate the role of macrophage PPARy in regulating the response of the macrophage to dietary and genetic interventions that lead to development of atherosclerosis and insulin resistance. These studies are expected to provide new insights into pathogenic programs of lipid metabolism in the macrophage and identify new targets for therapeutic intervention. Two specific aims are proposed: Specific Aim 1. Define the role of macrophage PPARy in mediating the effects of TZDs on foam cell formation in LDLR KO mice and define the transcriptomic and lipidomic changes correlated with these effects. Specific Aim 2. Define the role of macrophage PPARy in regulating macrophage responses to FFAs and the production of soluble factors that promote insulin resistance Macrophages play essential roles in normal immunity, but also contribute to the development of heart disease and diabetes. The procedures and experiments performed by this Bridge will enable the LIPID MAPS consortium to better understand how PPARy and clinically used anti-diabetic drugs exert therapeutic effects in macrophages. Knowledge gained from these studies may lead to the development of new strategies for the prevention and treatment of diabetes and heart disease.